Abstract
The first account on the dynamic features of Nef or negative factor, a small myristoylated protein located in the cytoplasm believes to increase HIV-1 viral titer level, is reported herein. Due to its major role in HIV-1 pathogenicity, Nef protein is considered an emerging target in anti-HIV drug design and discovery process. In this study, comparative long-range all-atom molecular dynamics simulations were employed for apo and bound protein to unveil molecular mechanism of HIV-Nef dimerization and inhibition. Results clearly revealed that B9, a newly discovered Nef inhibitor, binds at the dimeric interface of Nef protein and caused significant separation between orthogonally opposed residues, namely Asp108, Leu112 and Gln104. Large differences in magnitudes were observed in the radius of gyration (∼1.5 Å), per-residue fluctuation (∼2 Å), C-alpha deviations (∼2 Å) which confirm a comparatively more flexible nature of apo conformation due to rapid dimeric association. Compared to the bound conformer, a more globally correlated motion in case of apo structure of HIV-Nef confirms the process of dimeric association. This clearly highlights the process of inhibition as a result of ligand binding. The difference in principal component analysis (PCA) scatter plot and per-residue mobility plot across first two normal modes further justifies the same findings. The in-depth dynamic analyses of Nef protein presented in this report would serve crucial in understanding its function and inhibition mechanisms. Information on inhibitor binding mode would also assist in designing of potential inhibitors against this important HIV target.
Highlights
Since its emergence in early 1980s, the ‘‘global killer’’ acquired immunodeficiency syndrome (AIDS) has already proclaimed the lives of estimated 22 million people worldwide [1]
According to different documented reports, an estimated 34 million individuals live with HIV/AIDS worldwide [3,4]
The most effective therapeutic regimes consists of a multiple drug ‘‘cocktail’’, otherwise known as highly active antiretroviral therapy (HAART), approved by the Food and Drug Administration (FDA), which consists of several antiretroviral, targeting different enzymes in HIV life cycle [5]
Summary
Since its emergence in early 1980s, the ‘‘global killer’’ acquired immunodeficiency syndrome (AIDS) has already proclaimed the lives of estimated 22 million people worldwide [1]. The most effective therapeutic regimes consists of a multiple drug ‘‘cocktail’’, otherwise known as highly active antiretroviral therapy (HAART), approved by the Food and Drug Administration (FDA), which consists of several antiretroviral, targeting different enzymes in HIV life cycle [5]. These drugs mainly include: protease inhibitors (PIs), The development of resistant strains against almost all currently approved anti-retrovirals prompt researchers to find new drug targets, which can prove effective in reducing viral load from the host. As Nef is one of the accessory proteins of the HIV genome, it has a central role in the down-regulation of host immunity
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